Cannabinoid modulation of drug reward and the implications of marijuana legalization, Dan P. Covey et al., 2015

Cannabinoid modulation of drug reward and the implications of marijuana legalization

Dan P. Covey, Jennifer M. Wenzel, and Joseph F. Cheer

Brain Research, 2015  1628, 233–243.

doi : 10.1016/j.brainres.2014.11.034.



Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana’s illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana’s psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.

Keywords : endocannabinoids; marijuana; dopamine; ventral tegmental area; nucleus accumbens; mesolimbic


Section 1. Introduction

1.1. Marijuana: past, present, and future

The marijuana plant – classified as Cannabis sativa by Carl Linnaeus in 1753 – has been used by humans for thousands of years in various preparations: as fabric or rope, a source of oil, and as a drug (Abel, 1980; Robson, 2014). Various compounds within the plant have potent biological actions and medical utility, largely due to their anti-inflammatory and analgesic properties. But, humans have most commonly used marijuana for its psychoactive effects. Δ9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive compound in marijuana and is therefore responsible for its extraordinarily high rates of use. Due to concern regarding an unacceptable risk of addiction, the federal United States government declared marijuana illegal in 1937, which remains the case today. Nonetheless, more people currently use marijuana than all other illicit drugs combined (UNODC, 2014). The recent legalization of marijuana as an “over the counter” drug in Colorado, Washington, and Oregon, and as a prescription pharmaceutical in 21 other states, suggests that marijuana may gain an even greater influence on human behavior.

The primary target mediating Δ9-THC’s characteristic psychoactive and reinforcing properties is the cannabinoid type 1 (CB1) receptor (Huestis et al., 2001), which is now recognized as the most abundant G-protein coupled receptor in the brain (Kano et al., 2009). Yet, the CB1 receptor is not simply a neuronal target for Δ9-THC, but part of a larger endocannabinoid (eCB) system consisting of endogenous cannabinoid ligands (the endocannabinoids; eCBs) and their synthetic, degradative and transport machinery. This neuromodulatory network is involved in numerous brain functions, including: learning, memory, emotion, and motivated behavior (Solinas et al., 2008; Moreira and Lutz, 2008). The eCB system is also particularly important for regulating drug reinforcement. Indeed, CB1 receptors shape synaptic activity in the mesolimbic dopamine system to promote cue-directed reward seeking. Abused drugs exploit this adaptive function by supporting long-term alterations in the synaptic regulation of mesolimbic dopamine function that promote reward seeking. An improved understanding of these mechanisms has the potential to better inform future marijuana policy and the use or development of more effective pharmacological approaches for treating disorders of motivation.

1.2. High on cues: eCB regulation of drug seeking

The overvaluation of drug-paired environmental cues (e.g., paraphernalia) motivates drug use and is a critical factor driving relapse following drug abstinence (Childress et al., 1993; Hyman et al., 2006). A general role for the eCB system in conditioned drug-seeking has been proposed (De Vries et al., 2005; Fattore et al., 2007; Lupica and Riegel, 2005). This is supported by the ability of CB1 agonists, including Δ9-THC, to reinstate extinguished drug-seeking behavior for cannabinoids (Justinova et al., 2008; Spano et al., 2004), opioids (De Vries et al., 2003; Fattore, et al., 2005), ethanol (Lopez-Moreno et al., 2004), nicotine (Biala et al., 2009), and cocaine (De Vries et al., 2001). Additionally, CB1 receptor antagonists potently attenuate cue- or drug-induced reinstatement of drug seeking for Δ9-THC (Justinova et al., 2008), heroin (De Vries et al., 2003; Fattore et al., 2005), ethanol (Cippitelli et al., 2005; Economidou et al., 2006), nicotine (Cohen et al., 2005; De Vries et al., 2005), and cocaine (De Vries et al., 2001; Xi et al., 2006). Thus, CB1 receptor signaling supports the conditioned reinforcing properties of drug-paired cues, and pharmacologically increasing or decreasing CB1 receptor activation can increase or decrease drug seeking, respectively. Below, we will briefly describe the unique mechanisms by which eCBs regulate synaptic function and thereby exert such control over specific behaviors (Section 3). We will then describe how eCB regulation of the mesolimbic dopamine system supports cue-directed reward seeking. This occurs via CB1-dependent modulation of phasic dopamine cell firing (Section 4) and the impact of dopamine release on forebrain target neurons (Section 5). This will lead to a description of how this process can be exploited by abused drugs to support drug use (Section 6), and how this process can also be exploited to support better treatments for drug abuse and addiction (Section 7).

Section 2. eCB signaling mechanisms: General overview

Insight into the neuronal actions of marijuana began in the early 1990s following the identification of the CB1 receptor (Devane et al., 1988; Herkenham et al., 1991; Matsuda et al., 1990). Its first endogenous ligand was isolated soon after and identified as arachidonyl ethanolamine and named anandamide based on the Sanskrit word ananda for “bliss” (Devane et al., 1992). 2-arachidonoylglycerol (2-AG) was later identified as another natural ligand for the CB1 receptor (Sugiura et al., 1995). Both eCBs are synthesized from membrane phospholipids and their release mechanisms differ from that of “classical” neurotransmitters for two main reasons. First, the synthetic enzymes are localized to postsynaptic cell membranes across from CB1 receptors located on presynaptic terminals (Matyas et al., 2008; Uchigashima et al., 2007), indicating a retrograde release mechanism. Second, the lipophilic nature of eCBs precludes vesicular storage, necessitating a mechanism for translating extracellular activity into eCB synthesis and release.